Oligonucleotides conjugated to oleic acid and uses thereof

Abstract

The invention provides oligonucleotide and/or oligonucleotide analogue molecules that are antagonists of a microRNA, preferably antagonists of human microRNAs hsa-miR-23b-3p and hsa-miR-218-5p, that comprise a mixture of phosphorothioate and phosphodiester linkages, and that are conjugated to at least one oleic acid molecule. Inhibiting these microRNAs allows to increase the endogenous levels of the corresponding proteins MBNL1 and/or MBNL2. The present invention further provides compositions comprising said oligonucleotides and/or oligonucleotide analogue molecules and their uses for the treatment and prevention of DM in a subject in need thereof.

The invention claimed is: 
     
       1. An oligonucleotide molecule consisting of SEQ ID NOs: 22, 23, or 25, wherein the 3′ terminal nucleotide in each of said SEQ ID NOs: 22, 23, and 25 is conjugated to a spacer molecule, wherein the spacer molecule is conjugated to an oleic acid, and wherein the spacer molecule is selected from the group consisting of NHC3, NHC5, NHC6, and threoninol. 
     
     
       2. The oligonucleotide molecule according to  claim 1 , consisting of SEQ ID NO: 3. 
     
     
       3. The oligonucleotide molecule according to  claim 1 , consisting of SEQ ID NO: 4. 
     
     
       4. The oligonucleotide molecule according to  claim 1 , consisting of SEQ ID NO: 7. 
     
     
       5. A pharmaceutical composition, comprising one or more oligonucleotide molecules as defined in  claim 1 , and a pharmaceutically acceptable carrier or excipient, or a combination thereof. 
     
     
       6. The pharmaceutical composition of  claim 5 , comprising an oligonucleotide molecule consisting of SEQ ID NO: 3. 
     
     
       7. The pharmaceutical composition of  claim 5 , comprising an oligonucleotide molecule consisting of SEQ ID NO: 4. 
     
     
       8. The pharmaceutical composition of  claim 5 , comprising an oligonucleotide molecule consisting of SEQ ID NO: 7. 
     
     
       9. A method of treating Myotonic dystrophy type 1 (DM1) in a subject, comprising administering the pharmaceutical composition of  claim 5  to a subject in need thereof. 
     
     
       10. The method of  claim 9 , wherein the pharmaceutical composition comprises an oligonucleotide molecule consisting of SEQ ID NO: 3. 
     
     
       11. The method of  claim 9 , wherein the pharmaceutical composition comprises an oligonucleotide molecule consisting of SEQ ID NO: 4. 
     
     
       12. The method of  claim 9 , wherein the pharmaceutical composition comprises an oligonucleotide molecule consisting of SEQ ID NO: 7. 
     
     
       13. The oligonucleotide molecule of  claim 1 , wherein the oligonucleotide molecule is an antimiR. 
     
     
       14. A method of delivering the pharmaceutical composition of  claim 5  to the muscles and/or CNS of a subject, comprising administering the pharmaceutical composition of  claim 5  to the subject in need thereof. 
     
     
       15. The method of  claim 14 , wherein the pharmaceutical composition comprises an oligonucleotide molecule consisting of SEQ ID NO: 3. 
     
     
       16. The method of  claim 14 , wherein the pharmaceutical composition comprises an oligonucleotide molecule consisting of SEQ ID NO: 4. 
     
     
       17. The method of  claim 14 , wherein the pharmaceutical composition comprises an oligonucleotide molecule consisting of SEQ ID NO: 7.